tbuckley/cabot-search huggingface dataset:
Abstract 4915: Sensitivity to NAMPT inhibition: <i>In vitro</i> and <i>in vivo</i> characterization in ovarian cancer
Authors: Jenny J. Hong, Martina S. McDermott, Neil A. O'Brien, Enrique Guandique, Tong Luo, Dennis J. Slamon
Journal: Cancer Research (2023)

Abstract Previous in vitro work on determining the unique sensitivities of various cancers to nicotinamide phosphoribosyltransferase inhibitors (NAMPTis) has demonstrated promising effects of treating cancer cells with NAMPTis such as FK866 and KPT9274. These inhibitors act by disrupting cellular energy metabolism and reducing intracellular NAD+ levels. NAMPT inhibition thereby suppresses the proliferation of cancer cells which depend more heavily on the NAMPT enzyme to produce NAD+ than noncancerous cells. Using pan-cancer in vitro screens in a large panel of molecularly characterized cell lines (n = 496) we identified a subset of ovarian cancer, a cancer with a high unmet need due to lack of diverse targeted therapies, as being extremely sensitive to NAMPT inhibition. Subsequent in vivo work using CD-1 nude mice demonstrate that NAMPT inhibitors can successfully reduce the ovarian tumor burden and may be an effective treatment option of some ovarian cancers. Moreover, NAD+’s function as a substrate to the poly ADP-ribose polymerase (PARP) enzyme makes NAMPTis rational candidates for including in combination therapies with PARP inhibitors, several of which are approved for maintenance therapy for ovarian cancer. By using NAMPTis to disrupt the cellular metabolic process while simultaneously inhibiting PARP activity, an essential DNA damage repair enzyme, it is possible to exploit the dependence of ovarian cancer cells on functional PARP activity. This is particularly important in homologous recombination deficient subtypes. In addition to a synergistic growth inhibitory response in ovarian cancer cells, preclinical combination studies of NAMPTis with olaparib, an approved PARP inhibitor, exhibited higher levels of DNA damage accumulation than with single drug treatments. Our in vitro and in vivo characterizations of NAMPT inhibition suggest that NAMPTis as either single agents or in combination treatments with PARP inhibitors should be investigated further as potential treatment options for ovarian cancer patient populations. Citation Format: Jenny J. Hong, Martina S. McDermott, Neil A. O'Brien, Enrique Guandique, Tong Luo, Dennis J. Slamon. Sensitivity to NAMPT inhibition: In vitro and in vivo characterization in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4915.
Abstract 4133: OncoTAM, a comprehensive preclinical platform to explore macrophages as key drivers of cancer progression and develop new therapies against tumor-associated-macrophages
Authors: Caroline Mignard, Damien France, Francis Bichat, Nicolas Legrand, Olivier Duchamp
Journal: Cancer Research (2023)

Abstract Tumor-Associated Macrophages (TAMs) play an important role in the development of tumors, modulation of neoangiogenesis, immune suppression, and metastasis. A high infiltration of macrophages in the tumor is also correlated with a poor prognosis in several cancer types. Therefore, they became an attractive target for cancer immunotherapies. Several macrophage-targeting approaches in anticancer therapy are under development, including TAM depletion, inhibition of new TAM differentiation, or re-education of TAM activation for cancer cell phagocytosis. In this presentation, we will share different examples of in vitro assays and in vivo models we are implementing to support preclinical development of novel TAM-targeting strategies. Antibody-dependent cellular phagocytosis (ADCP) has been used to demonstrate one crucial mechanism of action of different antibody (Ab) therapies targeting macrophages. Some of these Ab (including anti-CSF1) have then been tested in syngeneic in vivo tumor models. To reach this goal, we demonstrated that the tumor implantation site in mice (subcutaneous vs orthotopic) could impact the polarization of macrophages (M1 vs M2). Differences in the ratio of M1 and M2 subtypes infiltrating the PAN-02 pancreatic murine tumors were observed, and anti-CSF1 antibodies increased the survival of mice bearing orthotopic Renca murine kidney tumor by eliminating TAMs. Additionally, in xenograft models of human breast tumors in NOD-SCID mice, the eradication of TAMs by anti-CSF1R clearly demonstrated the importance of macrophages in the tumor progression and in the anti-tumor efficacy of Abs mediated by macrophages. By using an orthotopic Hepa1-6 murine liver cancer model, we showed high antitumor efficacy of compounds targeting the STAT6 pathway by reprogramming immunosuppressive TAMs into an M1 phenotype that promotes the induction of a cytotoxic immune response. For compounds displaying no cross-reactivity with murine target, we developed models and characterized the TAMs in breast, colon, melanoma and head &amp; neck PDX and CDX tumors in different huCD34-engrafted mouse models. Altogether, the panel of in vitro assays and in vivo tumor models in OncoTAM should be useful to provide insights on the mechanism of action and antitumor efficacy of novel immune-oncology strategies targeting macrophages. Citation Format: Caroline Mignard, Damien France, Francis Bichat, Nicolas Legrand, Olivier Duchamp. OncoTAM, a comprehensive preclinical platform to explore macrophages as key drivers of cancer progression and develop new therapies against tumor-associated-macrophages. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4133.
Abstract 4914: Role of ClpP in the anti-cancer effects of imipridone ONC201 and ONC206
Authors: Andrew Lee, Cristina Maranto, Scott Foster, Sara Morrow, Joshua E. Allen, Randall Lanier, Phiroze Sethna, Varun V. Prabhu
Journal: Cancer Research (2023)

Abstract ONC201 is the first bitopic dopamine receptor D2 (DRD2) antagonist and allosteric mitochondrial protease ClpP agonist. Downstream of target engagement, ONC201 activates the integrated stress response pathway resulting in selective tumor cell death. ONC201 is well tolerated and induces durable tumor regressions in H3 K27M-mutant glioma patients. ONC206, a derivative of ONC201 currently in Phase I trials for adult and pediatric brain tumors, is also a bitopic DRD2 antagonist and ClpP agonist with nanomolar potency. We further evaluated in vitro efficacy and mechanism of action specific to ClpP for ONC206 and investigated acquired resistance to ONC201 and ONC206. FITC-casein and peptide degradation assays confirmed that ONC206 acts as an agonist of human ClpP with enhanced potency relative to ONC201. Broad efficacy in the nanomolar range for ONC206 (GI50 &amp;lt;78-889nM, 72h) was observed in 1,088 Genomics of Drug Sensitivity in Cancer (GDSC) cancer cell lines with increased sensitivity in cell lines exhibiting high ClpP mRNA expression. Among solid tumors, nervous system-related cell lines were particularly sensitive. Gene Expression Profiling Interactive Analysis (GEPIA) database analysis showed ClpP mRNA was overexpressed in glioblastoma cells relative to normal cells. GDSC observations were confirmed in glioblastoma (GBM) (T98G, A172, U87MG), H3.3 K27M mutant diffuse intrinsic pontine glioma (DIPG) (SF8628, SF7761) and astrocytoma (H4, U118MG) cell lines. ONC206 was more potent than ONC201 in cell viability assays for all glioma lines tested. SF8628 cells with a CRISPR-mediated ClpP knockout were shown to demonstrate resistance to both ONC201 and ONC206. Polyclonal resistant cell lines were generated through prolonged passaging in increasing concentrations of ONC201 or ONC206 (SF8628 and T98G cells). Cells with acquired resistance to ONC201 (ONC201Res) or ONC206 (ONC206Res) showed cross resistance to both imipridones. Time-stability of resistance was confirmed by removing drug for 2 to 4 weeks and retesting. RNAseq analysis revealed upregulation of the integrated stress response with imipridone treatment in T98G parental cells but not resistant clones. Whole genome sequencing revealed ClpP mutations in both ONC201Res and ONC206Res cells. Our results confirm the role of ClpP in the mechanism of action of ONC201 and ONC206 in tumor cells. Citation Format: Andrew Lee, Cristina Maranto, Scott Foster, Sara Morrow, Joshua E. Allen, Randall Lanier, Phiroze Sethna, Varun V. Prabhu. Role of ClpP in the anti-cancer effects of imipridone ONC201 and ONC206. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4914.
Abstract 4913: Enhancer RNA profiles predict sensitivity to a novel GPX4 inhibitor
Authors: Timothy Read, David Simpson, Jenna Rimel, Christy Rhine, Casey Pham, Cole Liechty, Eric Martin, Joey Azofeifa
Journal: Cancer Research (2023)

Abstract Inhibition of the GPX4 enzyme leads to the rapid accumulation of toxic lipid peroxides and cell death through a process known as ferroptosis. This mechanism has recently garnered significant attention in the field of oncology because many difficult-to-treat tumor types are particularly susceptible to this non-canonical form of cell death. However, robust biomarkers that predict sensitivity to ferroptosis are needed to help select well-defined tumor subtypes and patient segments that are likely to respond to GPX4-targeting. Our nascent RNA platform measures the active transcription of not only protein-coding transcripts, but also transcripts initiating from enhancer regions (enhancer RNAs) critical for defining cell type. We reasoned that these data could afford the unique opportunity to identify non-coding transcripts that could serve as novel biomarkers of sensitivity to ferroptosis. We recently discovered a potent and selective GPX4 inhibitor and profiled the compound for its ability to induce ferroptosis across a diverse group of cancer cell types. We chose several of the most sensitive and resistant cell lines for further examination using our nascent RNA platform and identified novel relationships between sensitivity to ferroptosis and cell-specific enhancer RNA profiles. Importantly, enhancer RNA profiles were more effective at stratifying sensitive and resistant cell lines than protein-coding gene expression. Using enhancer RNA expression profiles as biomarkers of drug sensitivity represents a novel strategy that could ultimately improve our ability to select patient cohorts more likely to benefit from emerging drug candidates and established therapeutics. Citation Format: Timothy Read, David Simpson, Jenna Rimel, Christy Rhine, Casey Pham, Cole Liechty, Eric Martin, Joey Azofeifa. Enhancer RNA profiles predict sensitivity to a novel GPX4 inhibitor. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4913.
Abstract 4382: Evolution of curative-intent lung cancer surgery in a 4 eras in the population-based mid-south quality of surgical resection (MS-QSR) cohort
Authors: Olawale Akinbobola, Meredith A. Ray, Carrie Fehnel, Andrea Saulsberry, Kourtney Dortch, Anberitha T. Matthews, Nicholas R. Faris, Caroline M. Godfrey, Matthew Smeltzer, Raymond U. Osarogiagbon
Journal: Cancer Research (2023)

Abstract Background. Most patients die within 5 years of curative-intent lung cancer surgery Differences in surgical quality and cancer biology drive long-term overall survival (OS) differences after curative-intent resection. From 2009 onward, we implemented a sequence of interventions to improve surgical quality and pathologic evaluation in a regional population. We evaluated population-level surgical quality and OS in the MS-QSR cohort. Methods. We categorized the MS-QSR into 4 (approximately) 5-year eras: 1) 2004-08, baseline; 2) 2009-13 (quality feedback and pilot intervention studies); 3) 2014-18 (surgical intervention with a lymph node collection kit); 4) 2019-22 (dual surgical and pathology intervention with novel gross dissection method). We compared surgical quality and OS across eras using standard statistical methods. Results. Of 6,701 resections, 15%, 33%, 32%, and 20% were in Eras 1-4, respectively. American College of Surgeons Operative Standard 5.8 quality was attained in 4%, 22%, 45%, and 65% of resections in Eras 1-4, respectively; the International Association for the Study of Lung Cancer’s stringent definition of ‘complete resection’ was achieved in 0%, 9%, 20%, and 31%, respectively; 120-Day mortality rates were 10%, 9%, 7%, and 4%; 3-year OS rates were 49%, 64%, 71%, and 84%; 5-year OS, 34%, 52%, and 61%, in Eras 1-3 (too early for Era 4); p&amp;lt;0.0001 for all comparisons. Conclusion. Population-level surgical quality and OS have improved sequentially in parallel with implementation of interventions to surgical and pathology practices. The higher OS threshold in the MS-QSR creates a platform to interrogate the biologic drivers of surgical outcomes differences. Citation Format: Olawale Akinbobola, Meredith A. Ray, Carrie Fehnel, Andrea Saulsberry, Kourtney Dortch, Anberitha T. Matthews, Nicholas R. Faris, Caroline M. Godfrey, Matthew Smeltzer, Raymond U. Osarogiagbon. Evolution of curative-intent lung cancer surgery in a 4 eras in the population-based mid-south quality of surgical resection (MS-QSR) cohort. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4382.
Abstract 4134: Boosting anti-tumor immunity by promoting high endothelial venule and tertiary lymphoid structure formation in solid tumors via LTBR agonism
Authors: Disi An, Guoying Chen, Wei Wang, Katja Mohrs, David DiLillo, Christopher Daly, Gavin Thurston, John Lin, Namita Gupta, Mickey Atwal, Frank Kuhnert
Journal: Cancer Research (2023)

Abstract High endothelial venules (HEV) are specialized blood vessels that mediate lymphocyte trafficking to lymph nodes. Tertiary lymphoid structures (TLS) are ectopic lymphoid formations that develop in inflamed, infected or tumoral tissues. TLS contain HEV and B cell follicles surrounded by a T-cell zone and are characterized by abundant chemokine expression. The presence of TLS and HEV in solid tumors is positively correlated with patient survival in many cancer types, and may even be predictive of better response to immune-checkpoint blockade. However, the molecular mechanisms underlying the intratumoral HEV and TLS formation remain unclear. Using murine syngeneic tumor models, we found that systemic activation of lymphotoxin beta receptor (LTBR) with an agonistic antibody induced tumor-specific HEV formation, increased dendritic cell (DC) and T cell infiltration, and enhanced T cell activation in the tumor. In vitro assays revealed that LTBR agonism directly upregulated activation and maturation markers in bone marrow-derived DCs and promoted DC-mediated CD4 and CD8 T cell activation. Single agent LTBR agonist treatment attenuated Colon26 tumor growth in a CD8 T cell-dependent manner. In combination treatment studies, LTBR agonism further augmented anti-tumor efficacy of anti-PD1 and of CAR-T therapy. Notably, LTBR agonist mAb treatment upregulated the expression of TLS-related chemokines and induced TLS-like structures in approximately 20% of treated tumors. To enhance TLS induction, we generated syngeneic tumor models engineered to express several cytokines/chemokines and performed an in vivo screen for tumor-associated TLS formation. We identified some factors that in combination with LTBR agonism induced B cell enrichment and immature TLS formation, while others promoted robust TLS induction and anti-tumor effect. TLS formation induced by combined LTBR agonism and cytokine expression is associated with augmented anti-tumor responses to anti-CTLA-4 treatment. By studying anti-tumor mechanisms of LTBR agonism-mediated HEV and TLS formation, this work informs the future therapeutic strategies to boost T cell infiltration and activation in solid tumors. Citation Format: Disi An, Guoying Chen, Wei Wang, Katja Mohrs, David DiLillo, Christopher Daly, Gavin Thurston, John Lin, Namita Gupta, Mickey Atwal, Frank Kuhnert. Boosting anti-tumor immunity by promoting high endothelial venule and tertiary lymphoid structure formation in solid tumors via LTBR agonism. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4134.
Abstract 5089: Small molecule Bax activator enhances immunotherapy against lung cancer
Authors: Abu Syed Md Anisuzzaman, Muhammad Waliul Talukdar, Xingming Deng
Journal: Cancer Research (2023)

Abstract Induction of apoptosis is a critical mechanism underlying the durable efficacy of cancer treatment agents. Bax is a major proapoptotic protein whose activation is required for apoptotic cell death. We have recently discovered that small molecule Bax activator CYD-2-11 targets the S184 structural pocket in the c-terminal tail of Bax, directly activates its proapoptotic activity via conformational change and formation of Bax homo-oligomers in mitochondrial membranes. CYD-2-11 has potent anti-tumor activity against lung cancer in various animal models. Here we found that CYD-2-11 in combination with radiation, cisplatin or BH3 mimetic Bcl2 inhibitor venetoclax (ABT-199) synergistically suppressed tumor growth in non-small cell lung cancer (NSCLC) xenograft models. It is known that LKB1 mutations or deficiency are associated with therapeutic resistance to PD-1/PD-L1 checkpoint blockade immunotherapy. To test whether Bax activator CYD-2-11 reverses resistance to immunotherapy in immunologically “cold” genetically engineered LSL-KRASG12D LKB1 fl/fl (KL) mouse model, KL mice were treated with CYD-2-11, PD-L1 antibody or in combination. Results indicate that PD-L1 antibody alone has no significant anti-tumor effect in KL mice. CYD-2-11 alone can reduce tumor burden, but combination of CYD-2-11 with PD-L1 antibody has very strong synergistic effect and produces maximum efficacy in tumor burden reduction and significantly prolongs survival of KL mice. Mechanistically, combined treatment with CYD-2-11 and PD-L1 antibody enhances T cell infiltration in tumor tissues. These findings provide preclinical evidence for pharmacologic combinations of small molecule Bax activator with chemoradiotherapy, Bcl-2 inhibitor or PD-L1 antibody as novel strategies to treat lung cancer more effectively. Citation Format: Abu Syed Md Anisuzzaman, Muhammad Waliul Talukdar, Xingming Deng. Small molecule Bax activator enhances immunotherapy against lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5089.
Abstract 3305: Clinical significance of circZKSCAN1 RNA in human hepatocellular carcinoma
Authors: Minji Bang, Gyeonghwa Kim, Eun Hwangbo, Mi Yeon Jeon, Keun Hur
Journal: Cancer Research (2023)

Abstract Circular RNAs (CircRNAs) are type of noncoding RNAs without 5’ caps and 3’ tails that has been created by back splicing of mRNA. Recently, circRNAs are identified in many types of cancers, and its function has been elucidated as multiple miRNAs sponge. Hepatocellular carcinoma (HCC) is the most common type of malignancies. The incidence and mortality of HCC have been on the rise in recent years. Thus, it is necessary to identify further molecular mechanisms of HCC initiation and progression. In this study, we aim to investigate the clinical relevance of circRNAs encoded by the ZKSCAN1 (Zinc finger protein with KRAB and SCAN domains 1) gene in HCC.We analyzed clinical specimens from 100 pairs of HCC and corresponding normal liver (NL) tissues. Total RNAs were isolated from clinical tissues using qiagen kit. CircRNAs (circZKSCAN1) derived from ZKSCAN1 gene. The expression levels were determined by quantitative real-time PCR (qRT-PCR), and its expression was normalized with GAPDH. In addition, we analyzed the correlation between circZKSCAN1 expression and various clinicopathological features of HCC patients.CircZKSCAN1 expression was significantly down-regulated in HCC tissues compared to corresponding NL tissues (P&amp;lt;0.001). In HCC patients, circZKSCAN1 expression was gradually suppressed according to state of malignant progression (P&amp;lt;0.010). Further correlation analysis showed that circZKSCAN1 expression was significantly associated with T-stage (P=0.009), TNM stage (P=0.002), BCLC stage (P=0.0467), and survival (P&amp;lt;0.001).Conclusively, we have determined clinical significances of circZKSCAN1 expression in HCC, which may provide clinical evidence for the potential of circZKSCAN1 as novel markers for diagnosis and predicting prognosis in HCC patients. Citation Format: Minji Bang, Gyeonghwa Kim, Eun Hwangbo, Mi Yeon Jeon, Keun Hur. Clinical significance of circZKSCAN1 RNA in human hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3305.